This is a competing continuation application of the project entitled Biological Effects of DHEA in the Elderly. As noted by the new title, COX Inhibition &Musculoskeletal Responses to Exercise, the application is a continuation of the study of factors that influence bone and muscle metabolism in aging. There is compelling evidence from studies of animals that prostaglandins (PG) are important factors in the bone formation and muscle protein synthesis responses to mechanical stress (i.e., exercise) and that cyclooxygenase (COX) is a key enzyme for mechanically-induced PG synthesis. Inhibition of COX activity, via non-steroidal anti- inflammatory drugs (NSAIDs), has been found to markedly blunt the osteogenic and myogenic responses to mechanical stress. There have been no prospective studies in humans of the potential effects of NSAIDs to impair the anabolic actions of exercise on bone and muscle. Accordingly, the global aim for the next award period is to determine whether use of ibuprofen before, but not after, exercise attenuates the anabolic effects of exercise training on bone and skeletal muscle in older women and men. To address this aim, women and men (n=150), aged 60-75 yr, will be recruited to participate in 9 months of supervised exercise training. The exercise program will be progressive in nature and include high-intensity weight lifting and weight-bearing exercises to stimulate increases in bone mineral density (BMD) and fat-free mass (FFM). Participants will be randomized to three treatment arms: ibuprofen 400 mg before exercise and placebo after (n=50), placebo before exercise and ibuprofen 400 mg after (n=50), and placebo before and after exercise (n=50). It is hypothesized that increases in lumbar spine BMD, total hip BMD, and fat-free mass (FFM) in response to 9 months of exercise training will be significantly less in women and men taking ibuprofen before exercise than in those taking ibuprofen after exercise or placebo. The importance of this study centers on the knowledge that declining levels of BMD and FFM are harbingers of osteoporosis, sarcopenia, and physical frailty in aging. High-intensity exercise that has the potential to improve BMD, muscle mass, strength, and physical function has become the cornerstone for the prevention and treatment of age-related physical disability. Therefore, knowledge of whether a drug as widely used as ibuprofen impairs the beneficial adaptations to exercise is deemed to be of high clinical significance.